An improved understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD) is needed to develop novel treatments for the disease which now accounts for over $40 billion in annual healthcare costs and recently surpassed stroke as the 3rd leading cause of death in the U.S. This is particularly true for the chronic bronchitis phenotype that afflicts ~2/3rd of COPD patients and leads to accelerated loss of lung function and excess mortality. Due to smoking, COPD patients exhibit reduced cystic fibrosis transmembrane conductance regulator (CFTR) activity, enhanced mucus production, and pronounced impairment of mucociliary clearance, resulting in a phenotype characteristic of 'acquired CFTR dysfunction'. Furthermore, we found CFTR dysfunction is independently associated with chronic bronchitis and can persist despite smoking cessation, suggesting it may be a major contributor to bronchitis pathogenesis. We have also shown acquired CFTR dysfunction can be reversed by CFTR potentiators in vitro by activating wild type CFTR, resulting in a robust increase in mucociliary transport. These data indicate that CFTR represents a potential therapeutic target to address mucus stasis in COPD patients with chronic bronchitis (nearly 10 million patients in the U.S. alone). However, before these treatments can be advanced, mechanistic insight into the contributions of acquired CFTR dysfunction to the physiologic impairments in COPD are required. Unfortunately, until now progress has been hampered by the absence of an animal model that exhibits the classical features of COPD- related bronchitis. Our preliminary data demonstrate that we have addressed this major barrier in COPD research by developing cigarette smoke exposed ferret as a large animal model that recapitulates pathologic and clinical evidence of human bronchitis, including time-dependent reductions in CFTR activity, delayed MCC, mucus retention and spontaneous respiratory infections. Furthermore, our laboratory has pioneered new techniques in ferrets to monitor (1) CFTR function in vivo, (2) airway surface liquid depth, ciliary beating, and mucociliary transport at the cellular level using one micron resolution optical coherence tomography (OCT) in vivo, and (3) clinically relevant outcomes such as cough, airway obstruction, and airway microbiology. We hypothesize that acquired CFTR dysfunction contributes to chronic bronchitis pathogenesis and clinical disease expression by reducing mucociliary clearance (Aim 1) and increasing susceptibility to bacterial infection by disrupting innate defense regulated by CFTR (Aim 2). Further, we hypothesize that acquired CFTR dysfunction can be pharmacologically ameliorated in vivo, resulting in improvements in chronic bronchitis and establishing the causative role of CFTR dysfunction in the disease (Aim 3). We are now poised to exploit the ferret model to make a major impact on our understanding of COPD pathogenesis; define the role of CFTR dysfunction in the disease; advance a novel treatment strategy of substantial impact, and characterize the first animal model representative of human chronic bronchitis, transforming our understanding of COPD.